A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles Into Functionalized Quinolines

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Article: Inprung, Nantachai, James, Michael J orcid.org/0000-0003-2591-0046, Taylor, Richard J K orcid.org/0000-0002-5880-2490 et al. (1 more author) (2021) A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines. Organic letters. ISSN 1523-7052 https://doi.org/10.1021/acs.orglett.1c00205

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[email protected] https://eprints.whiterose.ac.uk/ A thiol-mediated three-step ring expansion cascade for the conversion of indoles into functionalised quinolines Nantachai Inprung, Michael J. James*, Richard J. K. Taylor*, William P. Unsworth*

Department of Chemistry, University of York, Heslington, York, U.K., YO10 5DD ABSTRACT: An operationally simple, high yielding three-step cascade process is described for the direct conversion of indole- tethered ynones into functionalised quinolines. - -step dearomatising spirocyclisation, nucleophilic substitution and one-atom ring expansion reaction cascade under remarkably mild conditions. In addition, a novel route to thio-oxindolesA single is described, ‘multi tasking’ which thiol was reagentdiscovered is used by serendipity. to promote a three

Cascade reactions (chemical processes by which two or Scheme 1. Transformations of indole-tethered ynones. more consecutive reactions take place in a single pot-process, also wide utility in synthetic chemistry.1,2 Incorporating cascade reaction sequencesknown as into ‘tandem’ synthetic or ‘domino’ routes canreactions) significantly have improve the speed and ease with which complex target mol- ecules can be prepared, and often means that the direct han- dling of reactive, unstable and/or toxic species can be avoided by forming these intermediates in situ. This manuscript concerns a three-step cascade reaction sequence, starting from indole-tethered ynones 1 (Scheme 1). In recent years, ynones of this type have emerged as val- uable precursors for the preparation of a diverse array of molecular scaffolds.3-6 For example, our groups and others have shown that the activation of the alkyne moiety of 1 promotes efficient dearomatising spirocyclisation7,8 to form medicinally important spirocyclic indolenines 2;9,10 this is most commonly done using π-acidic catalysts (especially Ag(I) species), although Brønsted acids, palladium(II) com- plexes and electrophilic halogenation reagents can also be used (1 → 2, Scheme 1a, Step 1).3,11,12 Our groups have also shown that dearomatisation works well on 2-halogenated indoles (i.e. 1 where X = Cl, Br or I) and that the resulting We started by exploring reactivity of model 2-bromo indoleninyl halide products (i.e. 2 where X = Cl, Br or I) can ynone 1aBr with various reagents (NuH) that we thought be transformed further via reaction with nucleophiles, or might have the required acidity and nucleophilicity to pro- via Pd-catalysed cross-coupling, to substitute the halide for mote its conversion into a quinoline of the form 4. Phenol 15 various other groups (2 → 3, Scheme 1a, Step 2).5 Finally, was tested first, and added to a solution of 1aBr in DCE, but our groups and others have demonstrated that spirocyclic no reaction was observed after stirring at RT or 60 °C (en- indolenines of the form 3 will rearrange via a one-atom ring tries 1 and 2, Table 1). Next, TFA was included as an additive expansion reaction13 to form annulated quinolines, with in the reaction, which led to the consumption of the starting both acidic and basic reagents able to promote this trans- material, but the only tractable products observed were oxindole 7a (presumably formed via acid-mediated dearoma- formation (3 → 4, Scheme 1a, Step 3).6 tising spirocyclisation and hydrolysis of the resulting spiro- Efficient protocols for each of the individual steps repre- cycle 5a),5 and bromoquinoline 8, which likely formed via a sented in Scheme 1a are therefore established, but three- Bronsted acid-mediated rearrangement of 5a (c.f. step 3).6b steps are still required to generate functionalised quino- A more acidic NuH reagent, 4-nitrophenol, was tested but lines 4 from ynones 1. Quinolines are found in many mar- no reaction was observed at RT (entry 4), while at 60 °C the 14 keted drugs, as well as in various other applications. Based same side products 7a and 8 were formed (entry 5). We on a growing understanding of each of the three individual then decided to move on to species of similarly acidity to 3,5,6 processes discussed above, we recognised that certain phenol, but also more nucleophilic, and pleasingly, thiols16 reagents may be able to promote all three steps and enable were found to possess this attractive combination of prop- the transformation of 1 into 4 via a single-cascade process erties; using n-propyl thiol, no conversion was observed at (Scheme 1b); such a reagent would need to act as an acid to RT (entry 6), but excellent conversion into the desired quin- ø promote step 1, a nucleophile in step 2, and a Br nsted acid oline 4a was observed upon heating to 60 °C (entry 7). Fur- to promote step 3. The successful realisation of this strategy thermore, the more acidic thiophenol was able to promote is reported herein, with thiols emerging as the optimum the conversion of 1aBr into quinoline 4b smoothly at RT (en- - reagent class capable of promoting the entry 8). visaged cascade, under remarkably mild and operationally ‘multisimpletasking’ conditions. Table 1. Initial optimisation[a] was 4-NMe2-substituted ynone 1fBr; in this case, spirocyclic indoleninyl bromide 5b was isolated in 89% yield.19 Despite not delivering the expected quinoline, the isolation of spirocycle 5b does provide indirect mechanistic evidence for the intermediacy of indoleninyl halides in the reaction cascade (see later for discussion). Finally, by replacing the thiol with benzeneselenol, the analogous selenide product 4bSe was obtained in 62% yield. The unexpected isolation of thio-oxindole 9a during the synthesis of 4n prompted additional studies, in part to bet- ter understand this side reaction, but also to try and harness it productively, as a new way to make thio-oxindoles.20 Our theory for how thio-oxindole 9a formed is summarised in en- Nucleophile (NuH) Temp Outcome[b] Scheme 3a. The reaction is likely to have started as ex- try pected, and thus proceeded through the normal dearoma- 1 Phenol (Nu = PhO) RT No reaction tising spirocyclisation and nucleophilic substitution steps (i.e. steps 1 and 2). This would generate spirocycle 10, and 2 Phenol (Nu = PhO) 60 °C No reaction at this point, it appears that the route diverges, with some Phenol (Nu = PhO) with 7a (62%) 3 RT of the material going on to form quinoline 4n in the usual 1 equiv. TFA 8 (21%) way, and the rest undergoing debenzylation, either via an 4-Nitrophenol SN1-type pathway as drawn, or the analogous SN2-type 4 RT No reaction cleavage (not shown). To test this idea and improve the (Nu = 4-NO2C6H4O) yield of thio-oxindole 9a, the reaction was repeated using 4-Nitrophenol 7a (35%) the silylated thiol Ph3SiSH 11; the idea was that the weak 5 60 °C (Nu = 4-NO2C6H4O) 8 (45%) Si S would cleave more easily than the S Bn bond in 10, and n-Propyl thiol facilitate thio-oxindole formation via a desilylative mecha- 6 RT No reaction nism.– This idea worked well; the reaction– of ynone 1aBr with (Nu = n-PrS) Ph3SiSH 11 using the standard 60 °C procedure led to the n-Propyl thiol formation of thio-oxindole 9a in 82% isolated yield 7 60 °C 4a (95%) (Nu = n-PrS) (Scheme 3b). The same procedure was applied to other 2- Thiophenol halo-indole-tethered ynones, with thio-oxindoles 9b 9d 8 RT 4b (93%) (47 85%) prepared in the same way. (Nu = PhS) A proposed mechanism for the three-step cascade is out– - [a] 1aBr (1 equiv) and NuH (1.6 equiv) were stirred in DCE lined– in Scheme 4a. The cascade likely initiates with (0.1 M, degassed) for 20 h at the specified temperature. [b] dearomatising spirocyclisation, promoted by the relatively Yields are isolated material after column chromatography. acidic thiol (A B, step 1, Scheme 4a); protic acids have With conditions for the cascade established, attention been shown to promote spirocyclisation of related turned to examining the reaction scope. A range of aromatic ynones,3b,6b and→ the isolation of spirocyclic indoleninyl bro- thiols were tested (Scheme 2A), and all reacted well with mide 5b discussed earlier lends further support to this no- ynone 1aBrv; quinolines 4b k were all prepared in this man- tion. The resulting iminium-thiolate ion pair 2 may then un- ner, generally in high yield, under the standard RT condi- dergo facile nucleophilic substitution to afford substituted tions using a range of electronically– diverse substituted thi- spirocycle 12 (step 2).5 The rearrangement of 12 into 17 is ophenols. Other aliphatic thiols were also explored, with then thought to proceed via a previously studied acid-cata- quinolines 4a, and 4l–n prepared, although in this series lysed one-atom ring-expansion.6c heating to 60 °C was required. The yield for quinoline 4n Several control experiments were conducted to investi- was comparatively low (53%), with thio-oxindole 9a also gate this mechanism and the ordering of the steps. First, to formed in 27% yield; this unexpected side reaction is dis- probe whether the nucleophilic substitution step may pro- cussed later in the manuscript (see Scheme 3).17 ceed before spirocyclisation, 2-bromo-indole substrates Next, the 2-halide substituent was varied (Scheme 2B). lacking an ynone substituent (18 and 21) were each reacted Thus, 2-chloro (1aCl) and 2-iodo (1aI) analogues of ynone under the standard conditions with 4-methylbenzenethiol 1aBr were prepared,5 and both reacted smoothly with 4- (Scheme 4b, eq 1). In the case of indole 18, some bromide methylbenzenethiol to form quinoline 4d in high yield, al- substitution was indeed observed, with sulfide 19 formed beit at a higher reaction temperature (60 °C). Finally, we ex- in 31% yield. This confirms that nucleophilic substitution plored variation of the indole-tethered ynone component 1. directly on the indole is possible, although the yield was Four different additional 2-bromo-indole-tethered ynones low, and the major product was in fact the reduced product were successfully tested, with variations to the ynone and 20. Treating the analogous 3-methyl indole 21 in the same the indole motifs explored. For each ynone, a representative way resulted trace formation of 22 only. In view of these re- aliphatic (n-propylthiol) and aromatic thiol (4-methylben- sults, and given that no reduction products were observed zenethiol) were tested, with the expected quinoline prod- in any of the synthetic reactions, it seems unlikely that nu- ucts 4o–v to be isolated successfully in all cases.18 The only cleophilic substitution precedes dearomatising spirocy- substrate tested that did not deliver the expected quinoline clisation.

Scheme 2. Scope of the three-step thiol-mediated cascade for the conversion of ynones 1 into quinolines 4.[a]

[a] 1 (1 equiv) and RSH (1.6 equiv) were stirred in DCE (0.1 M) for 20 h at RT unless specified. [b] reaction performed at 60 °C. HS-Tol = 4-methylbenzenethiol We then questioned whether the iminium-thiolate ion 60 °C. However, the quinoline product 4a could be formed pair B might first undergo ring expansion to form a quino- in high yield at RT upon the addition of 1.1 equivalents of line and that nucleophilic substitution follows this step. To 48% aq. HBr to spirocyclic sulfide 6a. This result suggests probe this idea, both indoleninyl bromide 5a and 2-bromo- that a strong Brønsted acid is required to promote the ring quinoline 8 were reacted with 4-methylbenzenethiol under expansion, and such an acid would only be present in the the standard reaction conditions. Interestingly, both reac- reaction following the nucleophilic substitution step (which tions afforded the expected quinoline product 4a in high generates HX), thus supporting the originally proposed or- yields (Scheme 4b, eqs 2 & 3), suggesting that the order of der of steps. Furthermore, the success of the series of thio- steps 2 and 3 could be interchanged. oxindole forming reactions described in Scheme 3 also sup- To investigate this idea further, a discrete sample of the ports the same pathway, because in these reactions the suc- substituted spirocyclic sulfide 6a was reacted with 4- cessful formation of spirocyclic products 9a d means that methylbenzenethiol under the standard reaction conditions nucleophilic substitution must have out-competed ring ex- (eq 4). No conversion into quinoline 4a was observed and pansion in these cases. – only 6a was recovered after stirring for 24 h at both RT and

Scheme 3. The conversion of ynones 1 into thio-oxin- [email protected]; [email protected]; wil- doles 9 via a desilylative cascade process.[a] [email protected] Scheme 4. Proposed mechanism and control reactions

[a] 1 (1 equiv) and thiol 11 (1.6 equiv) were stirred in DCE (0.1 M) for 20 h at 60 °C.

Considering all these observations, we can be confident that the first step of the cascade is a thiol-promoted dearomatising spirocyclisation (step 1). The next step is most likely to be nucleophilic substitution (step 2) of the re- sultant iminium-thiolate ion pair, which generates a strong Brønsted acid (HBr) in situ. This acid then promotes a one- atom ring expansion (step 3) to form a stable aromatic quinoline product 4. Some interchange in the ordering of steps 2 and 3 cannot be ruled out once a reasonable concentration of HBr has built up in the reaction, however. In summary, a three-step cascade process has been developed that allows for the direct conversion of 2-halo-indole- tethered ynones into substituted quinolines. The key to the process is the use of thiols as multi-tasking reagents able to promote dearomatising spirocyclisation and nucleophilic substitution directly, as well promoting‘ a one’ atom ring ex- Author Contributions pansion indirectly, via the formation of a strong Brønsted The manuscript was written through contributions of all au- acid (HBr) in situ. The reactions are very simple to per- thors form21 and are typically high yielding, enabling the facile synthesis of a diverse array of functionalised quinolines. Funding Sources They are also easily scalable; for example, quinoline 4d was The Leverhulme Trust (ECF-2019-135) formed in 97% yield on 1 mmol scale (see ESI). In addition, a related route to thio-oxindoles was also developed follow- ACKNOWLEDGMENT ing a serendipitous discovery of an unexpected side reac- The authors would like to thank the Development and Promo- tion. tion of Science and Technology Talents Project (DPST), Royal Thai Government. (N.I. EP/N035119/1), the University of York ASSOCIATED CONTENT and the Leverhulme Trust (for an Early Career Fellowship, ECF- Supporting Information. Experimental procedures, charac- 2019-135, M.J.J.) for financial support. We are also grateful for terisation and copies of 1H and 13C NMR spectra for all com- the provision of an Eleanor Dodson Fellowship (to W.P.U.). We pounds featured in this manuscript. This material is available would also like to thank Dr Victor Chechik (University of York) free of charge via the Internet at http://pubs.acs.org for helpful discussions concerning the mechanism, and Theo Tanner (X-ray crystallography service, University of York) for AUTHOR INFORMATION collecting and processing the X-ray data. Corresponding Author REFERENCES

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SpirocyclicJ. K.; Unswor Indole-th, W. Strieth-Kalthoff, F.; Henkel, C.; Teders, M.; Kahnt, A.; nines and Carbazoles. Org. Lett. 2015, 17, 4372 4375. Knolle, W.; Gómez-Suárez, A.; Dirian, K.; Alex, W.; Bergan- (b) Magné, V.; Blanchard, F.; Marinetti, A.; Voituriez, A.; der, K.; Daniliuc, C. G.; Abel, B.; Guldi, D. M.; Glorius, F. Dis- Guinchard, X. – covery of Unforeseen Energy-Transfer-Based Transfor- N mations Using a Combined Screening Approach. Chem, NSynthesis of Spiro[piperidine-3,3′-oxin-Adv. 2019, 5, 2183. Synth.doles] Catalvia Gold(I)-Catalyzed. 2016, 358, 3355 Dearomatization3361; (c) Magné, of V.; Mari--Pro- 18) CCDC 2054407 contains the crystallographic data for pargyl-nettim, A.; and Gandon, -Homoallenyl-2-bromotryptamines. V.; Voituriez, A.; Guinchard, X. Synt he- compound 4v, see: www.ccdc.cam.ac.uk/data_re- – quest/cif lyzed Cyclizations of N Adv. 19) The reason for this difference is not fully clear. Solubility sisSynth. of SpiroindoleninesCatal. 2017, 359, 4036via Regioselective4042; (d) He, Gold(I)-Cata-Y.; Li, Z.; Rob- differences and/or changes to the electronic properties eyns, K.; Van Meervelt, L.;-Propargyl Van der Eycken, Tryptamines. E. V. of the ynone may both have had an influence, while the Catalyzed Domino Cyclization– Enabling Rapid Construc- relatively basic aniline group may also have altered the tion of Diverse Polyheterocyclic Frameworks. AAngew. Gold- pH balance and affected proton transfer in the reaction. Chem. Int. Ed. 2018, 57, 272 276; (e) Zhang, Z.; Smal, V.; Notably, in previous studies we have found that other 4- Retailleau, P.; Voituriez, A.; Frison, G.; Marinetti, A.; Guin- NMe2-substituted ynones have also reacted differently to chard, X. Tethered Counterion-Directed– Catalysis: Merg- other seemingly similar substrates in the series (see ref- ing the Chiral Ion-Pairing and Bifunctional Ligand Strat- erence 6a) egies in Enantioselective Gold(I) Catalysis. J. Am. Chem. 20) For background and biological properties of thio-oxin- Soc. 2020, 142, 3797 3805. doles and related oxindoles, see: Hurst, T. E.; Gorman, R. 13) (a) Unsworth, W. P.; Donald, J. R. Ring expansion reac- M. Drouhin, P.; Perry, A.; Taylor, R. J. K. A Direct C H/Ar tions in the synthesis– of macrocycles and medium sized H Coupling Approach to Oxindoles, Thio-oxindoles, 3,4- rings. Chem. Eur. J. 2017, 23, 8780 8799; (b) Lawer, A.; Dihydro-1H-quinolin-2-ones, and 1,2,3,4-Tetrahydro-– – Rossi-Ashton, J. A.; Stephens, T. C.; Challis, B. J.; Epton, R. quinolines. Chem. Eur. J. 2014, 20, 14603 14703 and ref- G.; Lynam, J. M.; Unsworth, W. P. Internal– Nucleophilic erence therein. Catalyst Mediated Cyclisation/Ring Expansion Cascades 21) Although degassed solvent was typically– used in this for the Synthesis of Medium-Sized Lactones and Lac- study to help ensure consistent results, this level of pre- tams. Angew. Chem., Int. Ed. 2019, 58, 13942 13947; (c) caution is generally not needed; for example, the conver- Clarke, A. K.; Unsworth, W. P. A happy medium: the syn- sion of 1aBr into 4d worked in 98% yield when done thesis of medicinally important medium-sized– rings via without degassing. The insensitivity of the reaction to ox- ring expansion. Chem. Sci., 2020, 11, 2876 2881 ygen also suggests that alternative radical pathways (c.f. 14) For reviews and perspective on the applications and uses reference 4a) are unlikely to operate. In addition, it was of functionalised quinolines, see: (a) Kumar,– S.; Bawa, S.; found that ynone 1aBr does not react when treated with Gupta, H. Biological Activities of Quinoline Derivatives PhSSPh in place of PhSH under the standard RT condi- Mini Rev. Med. Chem. 2009, 9, 1648 1654; (b) Prajapati, tions, which further reduces the likelihood that the cas- S. M.; Patel, K. D.; Vekariya, R. H.; Panchal, S. N.; Patel, H. cade reaction involves thiyl radical intermediates. The D. Recent advances in the synthesis– of quinolines: a re- analogous reaction with PhSSPh and 1 equivalent of HBr view. RSC Adv. 2014, 4, 24463 24476; (c) Marella, A.; led only to the formation of products in which sulfur had Tanwar, O. P.; Saha, R.; Ali, M. R.; Srivastava, S.; Akhter, not been incorporated: 7a (18%) and 8 (72%). M.; Shaquiquzzaman, M.; Alam, M.– M. Quinoline: A versa- tile heterocyclic. Saudi Pharm. J., 2013, 21, 1 12.

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